Cancer is the consequence of an aberrant gain of cellular fitness linked to the accumulation of stress and cellular damage of acute intensity. This damage occasionally provides aberrant advantages to certain cells, which can eventually lead to cancer development. The Ink4/Arf locus and p53 are regarded as the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Ink4/Arf locus encodes three tumor suppressor genes p15Ink4b, p16Ink4a, and p14Arf (p19Arf in mice). On one hand, p15Ink4b and p16Ink4a (called Ink4 hereafter) inhibit the formation of the cyclin-dependent kinases (CDK4 and CDK6) and cyclinD complexes during the G1 phase of the cell cycle. Hence, they prevent the transcription of genes involved in the transition to S phase, importantly the Rb/E2F1 pathway, so regulating cell cycle progression. On the other hand, Arf exerts its tumor suppressive action by inhibiting Mdm2, a ubiquitin ligase considered the major p53 regulator, thereby contributing to the activation and stabilization of p53.

The Ink4/Rb and Arf/p53 pathways are major sensors of stress that play a crucial role in early detection and elimination of cells that have suffered different types of stress including oncogene activation, DNA damage, oxidative stress, etc. While the activation of Ink4/Rb pathway induces reversible cell cycle arrest or irreversible cellular senescence-associated changes, the activation of p53 elicits a cellular response that might vary from restoration of cellular homeostasis by a transient blockade of the cell cycle to allow for DNA repair, senescence, or apoptosis. The activation of these responses depends in a complex manner, on the intensity of the triggering stress and on the cellular context. In agreement with this damage protective role, the individual or combinatory deletion of these genes promotes cancer susceptibility in multiple tissues and contexts. On the contrary, enhanced Ink4/Arf and p53 activity preserves mice from spontaneous or chemically induced cancers.

Although cancer and aging may seem opposite processes, they can be regarded as two different manifestations of the same underlying process, namely the accumulation of cellular damage. Moreover, cancer and aging may share common origins. There are several genetic or pharmacological manipulations that simultaneously modulate cancer and aging. These proofs demonstrate that cancer protection and longevity can be simultaneously modulated using different strategies and molecular mechanisms. In recent years, this is deepening the knowledge of the implications that the Ink4/Rb and Arf/p53 pathways have on the management of cellular damage associated with the aging process. The observation that several manipulations simultaneously modulate longevity and cancer protection establishes an interesting parallel with the expression of members of the Ink4/Rb and Arf/p53 pathways, which are silent or very low during development and postnatal life, while progressively increase from adulthood to old age in a broad range of tissues and species.

There is little additional information regarding p53 and aging in human, yet there is no evidence of a pro-aging function. Indeed, it has been documented that p53 is not involved in human premature aging disorders such as Hutchinson-Gilford Progeria, and it has been postulated that well-preserved p53-mediated responses are likely a key factor contributing to protection from diseases and cancer in centenarians. The above raises the possibility that Ink4/Rb and Arf/p53 pathways might have a role in aging. Thus, stress conditions cause an accumulation of DNA damage at the cellular level. Ultimately, it leads to the final activation of the Ink4/Rb and Arf/p53 pathways in order to achieve various adaptive responses to this situation. Amidst such responses is the transient block of the cellular cycle to try to repair the damage, inducing a state of senescence, or even apoptosis. Therefore, the empowerment of Ink4/Rb and Arf/p53 pathways might play an important role not only on surveillance and suppression of tumors, but also on the accumulation of cellular damage and aging. Therefore, it is reasonable to surmise that Ink4/Rb and Arf/p53 play a role also in the response to age-associated chronic stress and consequently affects aging. As activation of the Ink4/Rb and Arf/p53 pathways triggers a protective mechanism against tumor-induced stresses, they could also have anti-aging activity by alleviating the load of age-associated damage.

Significant efforts have been made to determine the impact of Ink4/Rb and Arf/p53 tumor suppressor pathways. While their protective function against cancer is firmly established, their role in aging remains controversial. In mice, it has been demonstrated that modest increases of regulated Arf/p53 activity are anti-aging while deregulated activation of p53 promotes aging. These observations are not in conflict per se and indicate that the activity of Arf/p53 could be beneficial or detrimental for aging depending on their intensity and regulation. It has recently been demonstrated that these effects are mediated through the activity of stem cells, indicating the concept of a reciprocal trade between tumor suppression, aging, and stem cell biology. Based on this, we postulate a model by which high or deregulated Arf/p53 impacts on lifespan by a decline in tissue stem cell regenerative function, but modest and regulated increases in Arf/p53 result in systemic organismal benefits ameliorating stem cell aging and maintaining tissue homeostasis. Additional work is necessary to establish the detail role and mechanism of action of p16Ink4a in aging and stem cell biology.

Growing organs from one species in the body of another may one day relieve transplant shortages. Now researchers show that islets from rat-grown mouse pancreases can reverse disease when transplanted into diabetic mice. The recipient animals required only days of immunosuppressive therapy to prevent rejection of the genetically matched organ rather than lifelong treatment. The success of the interspecies transplantation suggests that a similar technique could one day be used to generate matched, transplantable human organs in large animals like pigs and sheep.

To conduct the work, the researchers implanted mouse pluripotent stem cells, which can become any cell in the body, into early rat embryos. The rats had been genetically engineered to be unable to develop their own pancreas and were thus forced to rely on the mouse cells for the development of the organ. Once the rats were born and grown, the researchers transplanted the insulin-producing cells, which cluster together in groups called islets, from the rat-grown pancreases into mice genetically matched to the stem cells that formed the pancreas. These mice had been given a drug to cause them to develop diabetes.

The mouse pancreases were able to successfully regulate the rats' blood sugar levels, indicating they were functioning normally. Rejection of the mouse pancreases by the rats' immune systems was uncommon because the mouse cells were injected into the rat embryo prior to the development of immune tolerance, which is a period during development when the immune system is trained to recognize its own tissues as "self." Most of these mouse-derived organs grew to the size expected for a rat pancreas, rendering enough individual islets for transplantation. Next, the researchers transplanted 100 islets from the rat-grown pancreases back into mice with diabetes. Subsequently, these mice were able to successfully control their blood sugar levels for over 370 days, the researchers found. Because the transplanted islets contained some contaminating rat cells, the researchers treated each recipient mouse with immunosuppressive drugs for five days after transplant. After this time, however, the immunosuppression was stopped.

After about 10 months, the researchers removed the islets from a subset of the mice for inspection. "We examined them closely for the presence of any rat cells, but we found that the mouse's immune system had eliminated them. This is very promising for our hope to transplant human organs grown in animals because it suggests that any contaminating animal cells could be eliminated by the patient's immune system after transplant." Importantly, the researchers also did not see any signs of tumor formation or other abnormalities caused by the pluripotent mouse stem cells that formed the islets. Tumor formation is often a concern when pluripotent stem cells are used in an animal due to the cells' remarkable developmental plasticity. The researchers believe the lack of any signs of cancer is likely due to the fact that the mouse pluripotent stem cells were guided to generate a pancreas within the developing rat embryo, rather than coaxed to develop into islet cells in the laboratory. The researchers are working on similar animal-to-animal experiments to generate kidneys, livers and lungs.

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

Cellular senescence is a stress response characterized by the induction of a permanent cell cycle arrest. Senescence represents an important barrier to tumorigenesis by limiting the growth of potentially oncogenic cells. Senescence-associated growth arrest (SAGA) is accompanied by an overactive secretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP consists of numerous cytokines, growth factors, proteases and extracellular matrix components that, depending on the physiological context, can be either beneficial or deleterious. During early stages, SASP components promote the migration and infiltration of effector immune cells through the secretion of cytokines and facilitate tissue repair and remodeling by release of growth factors and proteases; however, in later stages, persistent senescent cells negatively impact the surrounding microenvironment by impairing tissue homeostasis through complex cell and non-cell autonomous effects.

In a cell-autonomous manner, selected SASP components such as interleukin (IL)-6 and IL-8 can reinforce SAGA through autocrine pathways. However, the same secreted components can act in paracrine signaling to neighboring cells, propagating the senescent phenotype and thus potentially hampering the regenerative capacity of surrounding tissue. Similarly, in a non-cell-autonomous manner, SASP cytokines promote infiltration of immune cells, yet persistent signaling can result in disruptive chronic inflammation, a hallmark of aging and major contributor to age-related dysfunctions. Indeed, senescent cells accumulate late in life and at sites of age-related pathologies, and genetic interventions enabling the effective clearance of senescent cells in genetically engineered animal models is sufficient to delay a number of age-related phenotypes.

Accordingly, a prolonged healthspan is obtained by pharmacological interventions using a novel class of drugs termed senolytics, used to selectively ablate senescent cells. Senolytic interventions not only demonstrated the feasibility of extending healthspan but also evidenced the alleviation of a wide range of pre-existent age-related symptoms including: improved cardiovascular function, reduced osteoporosis and frailty; enhanced adipogenesis, reduced lipotoxicity and increased insulin sensitivity; improved established vascular phenotypes associated with aging and chronic hypercholesterolemia; as well as radioprotection and rejuvenation of aged-tissue stem cells.

Although regeneration capacity deteriorates with age in mammals, it remains intact in other species such as salamanders. Surprisingly, salamanders show a significant induction of cellular senescence during limb regeneration; however, rapid and effective mechanisms of senescent cell clearance operate in regenerating tissues. Accordingly, the number of senescent cells does not increase upon aging, in contrast to mammals. However, very recently senescent cells have been shown to promote tissue regeneration also in mammals, probably through secretion of specific SASP factors. Thus, pharmacological or localized assisted immunological clearance of senescent cells might potentially aid regeneration of dysfunctional aged tissues.

The various beneficial effects resulting from the administration of drugs to selectively eliminate senescent cells, or suppress the deleterious aspects of the SASP, encourage their use in the treatment of age-related disabilities and chronic diseases as a group. Unfortunately, many challenges are still to be overcome for a successful drug development program, including increased selectivity and reduction of off-target effects. The optimization of therapeutic dosage in already approved drugs, now repurposed for aging interventions, appears promising in the reduction of unwanted side-effects, as demonstrated for rapamycin using lower intermittent doses. Additionally, the development of appropriate animal models capable of demonstrating the beneficial effects using clinically relative outcomes is imperative. These models would ideally be capable of distinguishing on-target from off-target effects to enable a correct assessment of safety and efficacy at a preclinical level, and ultimately grant their use in human clinical trials. In the near future, it is most likely that interventions against cellular senescence will only be prescribed on a case-by-case basis, for specific age-related dysfunctions, in patients with a favorable risk:benefit tradeoff; as is already the case in oncology where many identified senolytics are currently under investigation. Promisingly, however, human clinical trials are already underway to evaluate pharmaceutical impacts on longevity and human aging as a whole, extending our understanding on the human biology of aging and suggesting antiaging interventions could be closer than expected.

Let's say you replace a single neuron in your brain with one that functions thousands of times faster than its biological counterpart. Are you still you? You'd probably argue that you are, and even a significant speed bump in a single neuron is likely to go largely unnoticed by your conscious mind. Now, you replace a second neuron. Are you still you? Again, yes. You still feel like yourself. You still have the continuity of experience that typically defines individuality. You probably still don't notice a thing, and indeed, with only a couple of overachieving neurons, there wouldn't be much to notice. So, let's ramp it up. You replace a million neurons in your brain with these new, speedy versions, gradually over the course of several months. Sounds like a bunch, right? Not really; you've still only replaced 0.001% of your brain's natural neurons by most estimates. Are you still you?

You may find you're reading books a teensy bit faster now, and comprehending them more easily. An abstract math concept that once confused you now begins to make some sense. You're still very much human, though. But why stop there? You're feeling pretty good. You feel the tug of something greater calling you. Is it the curiosity, the siren call of improving one's own intelligence? You embark on a neurological enhancement regimen of two billion fancy new neurons every month for a year. After this time, you've got on the order of 24 billion artificial neurons in your head, or about a quarter of your brain.

Are you still you? Your feelings and emotions are still intact, as the new neurons don't somehow erase them; they just process them faster. Or they don't, depending upon your preference. About half-way through this year, you began noticing profound perceptual changes. You've developed a partially eidetic memory. Your head is awash in curiosity and wonder about the world, and you auto-didactically devour articles at a rapid clip. Within weeks you've attained a PhD-level knowledge of twenty subjects, effortlessly. All art becomes not just a moving experience, but an experience embedded in a transcendental web of associations with other, far-removed concepts. Synesthesia doesn't begin to cover what you're experiencing. But here's the thing; it's not overwhelming, not to your enhanced, composite brain and supercharged mind.

You reason (extraordinarily quickly at this point), that since you don't seem to have lost any of your internal experience, you should seek the limit or its limitlessness, and replace the rest of it. After all, at this point, everyone else is, too. It's getting harder to find work for someone who's only a quarter-upgraded. Over the next three years you continually add new digital neurons as your biological ones age, change, and die out. Are you still you? Following this, you are a genius by all traditional measures. Only the most advanced frontiers of mathematics and philosophy give you pause. Everything you've ever experienced, every thought that was ever recorded in your brain (biological or otherwise) is available for easy access in an instant.

Years pass. The same medical technology that allowed your neurons to be seamlessly replaced, aided and accelerated by a planet full of supersavants, has replaced much of your biological body as well. You're virtually immortal. Only virtually, of course, because speeding toward Earth at a ludicrous velocity is a comet the size of Greenland. There is general displeasure that the Earth will be destroyed (and just after we got smart and finally cleaned her up!), but there's a distinct lack of existential terror. Everyone will be safe, because they are leaving. How does a civilization, even a very clever one, evacuate billions of people from a planet in the space of years? It builds some very large machines that circle the Sun, and it uploads everyone to these machines. Uploads? People? Why sure, by now everyone has 100% electronic minds. These minds are simply software; in fact, they always were. Only now, they're imminently accessible, and more importantly, duplicable.

Billions of bits of minds of people are beamed across the solar system to where the computers and their enormous solar panels float, awaiting their guests. Of course, just as with your neuronal replacements all those years ago, this is a gradual process. As neurons are transferred, their counterparts in your skull are disabled. The only difference you feel is a significant lag, sometimes on the order of minutes, due to the millions of miles of distance between one half of your consciousness and the other. Eventually, the transfer is complete, and you wake up in a place looking very familiar. Are you still you?

Using a novel approach for imaging the movement of immune cells in living animals, researchers have identified what appear to be the initial steps leading to joint inflammation in a model of inflammatory arthritis. "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors. But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process. The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis."

Inflammatory arthritis includes a number of autoimmune diseases of the joints - including rheumatoid arthritis and lupus - and in many cases is caused by a type of inflammation called type III hypersensitivity. That reaction results when a localized accumulation of immune complexes - antibodies bound to their antigens - is deposited in tissue and sets off an inflammatory response involving the infiltration and activation of immune cells, initially the neutrophil. Current thinking regarding type III hypersensitivity is that immune cells within tissues sense the presence of these immune complexes (ICs) through specific receptor molecules and release inflammatory factors called cytokines that activate the endothelial cells lining adjacent blood vessels to promote the recruitment of neutrophils.

To better determine the role of specific chemoattractants in type III hypersensitivity, researchers used multiphoton intravital microscopy to follow in real time the development of IC-induced arthritis in a mouse model of rheumatoid arthritis. Their experiments revealed that the presence of ICs within the joint space induces the generation of complement C5a, a component of the innate immune system, which is then displayed on the inner walls of adjacent blood vessels. C5a directly initiates the adherence of neutrophils to the vessel walls through interaction with the C5a receptor on neutrophils, which then pass into the joint space and set off inflammation. Once the inflammatory process has been initiated, neutrophils within the joint space release interleukin-1, which induces cells lining the joint space to produce chemoattractants called chemokines that further facilitate the movement of neutrophils into the joint space. Neutrophils within the joint also directly produce chemokines that amplify the cells' recruitment to and survival within the joint space.

Most advocates of life extension report facing resistance to the idea of increased lifespans by medical means when trying to disseminate this idea among general public. Resistance manifests itself in many forms, ranging from concerns such as overpopulation to concerns about unequal access to life extending treatments. But the most unexpected thing is probably that people often don't want an increased lifespan at all. Surveys in different countries show, that when people are asked "how long would you like to live?", they often give a number equal to or slightly higher than the current life expectancy in a given country. But wait ... Isn't extending life for more decades a good thing that everyone should strive for? In reality we often do not see enough enthusiasm for the idea in general. So why is this?

It turns out that the reaction of general public to the idea depends on how the message is formulated. When only life extension is offered, without details of how healthy, mentally sound and good-looking an individual could become, people express less support for the idea. But when life extension is proposed as a combination of perfect physical and mental health, it changes the response dramatically, leading to many more people accepting the idea, and also showing support for the development of corresponding medical technologies. It is important to note, that there are also other factors that influence higher support for life extension and related medical innovations, reported by researchers. An interest in science, for example, appears to be the strongest predictor of a positive attitude towards medical interventions to extend life.

In some surveys, where the message did not include a promise of perfect health combined with longevity, males were found to be more likely to support life extension than females. Most likely, this can be explained by different perception of the risks. Males are found to be more likely to take the risks, so they can cope better with the risks emerging from using an innovative technology, when the long-term effects are still unknown and the volume of benefit is not clear. In other studies, however, when healthy life extension (with a "utopian" scenario) was offered, this difference between the sexes did not remain consistent, males and females were equally supportive of life extension technologies. It could be that a positive scenario does not engage the mechanisms of risk avoidance. But then, it means that solely by adding perfect health to life extension in our messages, we can significantly widen the number of our supporters. Studies like this illustrate the importance of analyzing how the nature of the message matters in furthering our cause. The advocates of rejuvenation biotechnology, including research groups and fundraisers for aging biology research, should carefully consider the messages they are using, as some of them are more efficient to encourage an informed and engaging discussion with society about the benefits of bringing aging under medical control.

Somatic mitochondrial DNA (mtDNA) damage has been associated with both normal aging and neurodegeneration. Accelerated mtDNA mutagenesis causes a premature aging phenotype in mice and somatic mtDNA deletions have been shown to accumulate with advancing age in post-mitotic tissues including the brain, heart and skeletal muscle. In the brain, the dopaminergic substantia nigra is particularly susceptible to somatic mtDNA deletions, which accumulate there at substantially higher levels compared with other areas of the brain. This predilection has led to the hypothesis that mtDNA damage plays a role in the pathogenesis of Parkinson disease (PD), where neurodegeneration of the substantia nigra is the main pathological hallmark and widely accepted as the cause of the cardinal clinical features.

mtDNA deletions were shown to accumulate at similar levels in both individuals with PD and healthy controls however, and therefore do not provide a sufficient explanation for the specific vulnerability of the substantia nigra in PD. Mice accumulating high levels of mtDNA deletion due to an error-prone mtDNA-polymerase (POLG) show a concomitant increase in mtDNA copy number which is associated with nigrostriatal survival and even resistance to mitochondrial respiratory chain complex-I inhibition. Although a similar protective mechanism has not yet been identified in humans, the importance of mtDNA copy-number regulation is highlighted by the vulnerability of the substantia nigra in inherited mtDNA-depletion disorders and the increased risk of PD associated with genetic variation in genes encoding key factors of mtDNA maintenance, such as the mtDNA polymerase γ (POLG) and mitochondrial transcription factor A (TFAM). Nevertheless, the precise mechanism by which mtDNA copy-number loss contributes to brain aging and neurodegeneration remains unclear.

We hypothesized that dopaminergic substantia nigra neurons in PD are rendered vulnerable to the effects of age-dependent mitochondrial mutagenesis due to an underlying dysregulation of mtDNA homeostasis. To test our hypothesis, we employed an integrative approach to study the complete spectrum of mtDNA changes in individual neurons from individuals with PD and controls. Our sample was derived from a population-based, prospectively collected and extensively characterized cohort. To ensure our sample was homogenous and representative for sporadic PD, we excluded known monogenic causes of PD by whole-exome sequencing. Neuropathological examination confirmed Lewy-body disease in all PD samples, whereas control samples were negative for neurodegenerative markers. Our results show that dopaminergic substantia nigra neurons of individuals with PD accumulate higher levels of somatic mtDNA deletions, but not point mutations, compared with age-matched controls. Moreover, in healthy individuals, mtDNA copy number increases with age, thus maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. Conversely, mtDNA copy number does not increase in individuals with PD, resulting in depletion of the wild-type mtDNA population. Our findings suggest that mtDNA homeostasis is impaired in the substantia nigra of individuals with PD.

Arguments against rejuvenation only sound reasonable because they appeal to our fears and to the blame-the-humans attitude of so many people. If you trust only your gut feelings and don't bother examining facts and data, anti-rejuvenation arguments can easily seem obviously true. Accepting an anti-rejuvenation argument requires far less mental work than understanding why the same argument isn't as sound as it appears, but that doesn't make anti-rejuvenation arguments any more 'obviously true' than their rebuttals. It is impossible to know for a fact whether or not rejuvenation will cause any given problem before we get there.

Proving that no problems will arise as a consequence of defeating ageing is not the point of rebutting objections to rejuvenation. That's not what any of my answers does. All they do is showing that objections to rejuvenation rely more often than not on fallacious reasoning, ignorance, fears, misconceptions, and wrong assumptions taken for established fact. In short, what we do when rebutting objections to rejuvenation is showing they aren't valid reasons to let ageing continue crippling and killing us. At the same time, answers to objections show why all those predictions of doom and gloom aren't as likely as they may appear. There's no certainty to be found anywhere, but this doesn't really matter-had we refrained from doing anything that wasn't proved to be 100% risk-free throughout history, we'd probably still be living in caves.

Remember: Objections to rejuvenation are about hypothetical future problems that are far from being certain. Ageing and all the suffering and deaths that come with it are a very tangible fact, happening here and now. This alone should be sufficient to forget about objections altogether and focus only on putting an end to ageing. However, rebutting objections has also another purpose: It fuels discussion. Apart from raising awareness of the problem of ageing and the feasibility of its defeat, discussion prepares us to face the new challenges an ageless future might bring. The way to a world without ageing is still long, which gives us all the time we need to prevent eternal dictators, overpopulation, and all sorts of dystopian scenarios from ever materialising.

Organovo, a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced a collaboration with the Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia to develop an architecturally correct kidney for potential therapeutic applications. The collaboration has been made possible by a generous gift from the Methuselah Foundationas part of its ongoing University 3D Bioprinter Program. "Partnerships with world-class institutions can accelerate groundbreaking work in finding cures for critical unmet disease needs and the development of implantable therapeutic tissues. This collaboration is another important step in this direction. With the devoted and ongoing support of the Methuselah Foundation, leading researchers are able to leverage Organovo's powerful technology platform to achieve significant breakthroughs."

We have developed an approach for recreating human kidney tissue from stem cells," said the Theme Director of Cell Biology at Murdoch Childrens Research Institute. "Using Organovo's bioprinter will give us the opportunity to bioprint these cells into a more accurate model of the kidney. While initially important for modelling disease and screening drugs, we hope that this is also the first step towards regenerative medicine for kidney disease. We are very grateful to Organovo and the Methuselah Foundation for this generous support, which will enable us to advance our research with the first Organovo bioprinter in the southern hemisphere." Under Methuselah Foundation's University 3D Bioprinter Program, Methuselah is donating at least 500,000 in direct funding to be divided among several institutions for Organovo bioprinter research projects. This funding will cover budgeted bioprinter costs and key aspects of project execution.

Significant progress has been made over the past 25 years in the development of in vitro-engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin, or for the establishment of in vitro human skin models. In this sense, laboratory-grown skin substitutes containing dermal and epidermal components offer a promising approach to skin engineering. In particular, a human plasma-based bilayered skin generated by our group, has been applied successfully to treat burns as well as traumatic and surgical wounds in a large number of patients in Spain. There are some aspects requiring improvements in the production process of this skin; for example, the relatively long time (three weeks) needed to produce the surface required to cover an extensive burn or a large wound, and the necessity to automatize and standardize a process currently performed manually. 3D bioprinting has emerged as a flexible tool in regenerative medicine and it provides a platform to address these challenges.

In the present study, we have used this technique to print a human bilayered skin using bioinks containing human plasma as well as primary human fibroblasts and keratinocytes that were obtained from skin biopsies. We were able to generate 100 cm2, a standard P100 tissue culture plate, of printed skin in less than 35 minutes (including the 30 minutes required for fibrin gelation). We have analysed the structure and function of the printed skin using histological and immunohistochemical methods, both in 3D in vitro cultures and after long-term transplantation to immunodeficient mice. In both cases, the generated skin was very similar to human skin and, furthermore, it was indistinguishable from bilayered dermo-epidermal equivalents, handmade in our laboratories. These results demonstrate that 3D bioprinting is a suitable technology to generate bioengineered skin for therapeutical and industrial applications in an automatized manner.

Today, a stroke usually leads to permanent disability - but in the future, the stroke-injured brain could be reparable by replacing dead cells with new, healthy neurons, using transplantation. Researchers have taken a step in that direction by showing that some neurons transplanted into the brains of stroke-injured rats were incorporated and responded correctly when the rat's muzzle and paws were touched. The study used human skin cells. These cells were re-programmed to the stem cell stage and then matured into the type of neurons normally found in the cerebral cortex.

A couple of years ago, the research team had already proven that transplanting this type of cells to the cerebral cortex enabled stroke-injured rats to move better. At the time, however, it was unclear whether the host brain really formed functioning connections with the transplanted nerve cells. Now the new study has proven that this is indeed the case. The research team used several advanced methods in the study - electron microscopy, virus-based tracing techniques, registration of activity in the transplanted cells and optogenetics. The results show that various parts of the host brain form normal, functioning connections with the transplanted neurons and that the latter change their activity when the animal's muzzle and paws are touched.

"This is the first time anyone has been able to show such a result. That some of the new nerve cells receive signals from the host brain in a normal way indicates that they have been incorporated into the stroke-injured rat's brain. In it, they have been able to replace some of the dead nerve cells. This is basic research, and it is not possible to say when we will be ready to start experiments on patients. But the objective is clear: to develop a treatment method which can repair the stroke-injured brain. Currently, there is no effective treatment which can restore function in a stroke patient once the first hours following a stroke have passed."

Under ordinary circumstances, the protein tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that damage brain cells. Such tangles are a hallmark of Alzheimer's and other neurodegenerative diseases. But researchers have shown that levels of the tau protein can be reduced - and some of the neurological damage caused by tau even reversed ­- by a synthetic molecule that targets the genetic instructions for building tau before the protein is made. The findings suggest that the molecule - known as an antisense oligonucleotide - potentially could treat neurodegenerative diseases characterized by abnormal tau, including Alzheimer's.

Researchers studied genetically modified mice that produce a mutant form of human tau that easily clumps together. These mice start showing tau tangles at around 6 months of age and exhibit some neuronal damage by 9 months. To reduce tau, the researchers used an antisense oligonucleotide, a kind of molecule that interferes with the instructions for building proteins. Genes in the DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to the messenger RNA and target it for destruction before the protein can be built. Such oligonucleotides can be designed to target the RNA for almost any protein.

The researchers administered a dose of the anti-tau oligonucleotide to 9-month-old mice every day for a month and then measured the amount of tau RNA, total tau protein and tangles of tau protein in their brains when the mice were 12 months old. The levels of all three were significantly reduced in the treated mice compared with mice that received a placebo. Importantly, levels of total tau and tau tangles in the brains of treated 12-month-old mice were lower than in untreated 9-month-old mice, suggesting that the treatment not only had stopped but reversed the buildup of tau.

By the time this strain of genetically modified mice reaches 9 months of age, the hippocampus - a part of the brain important for memory - typically is visibly shrunken and shows dying neurons. But with the oligonucleotide treatment, the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death. The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities. All of these functions can be impaired in people with Alzheimer's disease and other tau-related neurodegenerative diseases.

The researchers were intrigued by the possibility of designing studies to lower tau in people, but first they needed to see how the oligonucleotide worked in an animal more similar to people than a mouse. The researchers treated groups of healthy cynomolgus monkeys with two doses of placebo or oligonucleotide, one week apart, directly into the cerebrospinal fluid that surrounds the spinal cord and brain, just as would be done with human patients. Two weeks later, they measured the amount of tau protein and RNA in the monkeys' brains and cerebrospinal fluid. The oligonucleotide reduced both tau RNA and protein in the brain, and this reduction was mirrored in the cerebrospinal fluid.

Th first thing visitors to the Texas Heart Institute's Regenerative Medicine Research labs see is a pair of large photographs. In one, a lined hand of Denton Cooley, founder of the institute, who died last November, holds a mechanical heart much like the one that he was the first to implant into a human in 1969. In the other, Doris Taylor's gloved hand holds a pig's heart so stark-white, it matches her lab coat. It is a Ghost Heart, scrubbed clean of all cells, leaving only collagen, fibronectin and laminin, which provide a protein scaffold on which to build a new human heart very nearly from scratch. One day, it will cure far more patients with bum tickers than Cooley's earlier invention ever did.

Taylor and her 25-person multidisciplinary team decellularize seven or eight hearts, mostly from rats, a week, then inject the DNA-free scaffolds with stem cells. Because muscular heart cells do not divide, they cannot regenerate on their own like, say, the bladder, an organ which has been regenerated and implanted in humans. In the case of the heart, stem cells (as opposed to heart cells) adhere to the surface of the scaffold, growing into living, functioning organs inside machines known as bioreactors, which replicate the warm, oxygen-rich environment of a heart inside a mammal's body.

The goal, of course, is to build viable organs that will pump blood through an adult's body without assistance and without the threat of rejection, since the heart will be made with the recipient's own cells. Current testing in rats has involved implanting a second heart alongside the original, in hopes that the new organ will strengthen enough inside the body to take command. Taylor estimates that it will be only 10 or 15 years before a functioning heart is implanted into an adult (pediatric hearts are smaller and require less muscle, so that could happen sooner) - "if we do it right. And what I mean by that is that although it's sexy to be first, it's better to be best." Taylor expects a fully functioning liver made from a recipient's own cells will precede the heart by several years.

Exosomes are tiny membrane-enclosed packages that form inside of cells before getting expelled. Long thought of as part of a cellular disposal system, scientists have more recently discovered that exosomes are packed with proteins, lipids and gene-regulating RNA. Studies have shown that exosomes from one cell can be taken up by another by fusing with the target cell's membrane, spurring it to make new proteins. Exosomes also facilitate cell-to-cell interactions and play a signaling role, prompting research into their potential therapeutic effect.

A new study in rats shows that exosomes appear to protect cells in the retina, the light-sensitive tissue in the back of the eye. Researchers investigated the role of stem cell exosomes on retinal ganglion cells, a type of retinal cell that forms the optic nerve that carries visual information from the eye to the brain. The death of retinal ganglion cells leads to vision loss in glaucoma and other optic neuropathies. Stem cells have been the focus of therapeutic attempts to replace or repair tissues because of their ability to morph into any type of cell in the body. However, from a practical standpoint, using exosomes isolated from stem cells presents some key advantages over transplanting whole stem cells. Exosomes can be purified, stored and precisely dosed in ways that stem cells cannot.

Another important advantage of exosomes is they lack the risks associated with transplanting live stem cells into the eye, which can potentially lead to complications such as immune rejection and unwanted cell growth. In a rat glaucoma model, researchers studied the effects of exosomes isolated from bone marrow stem cells on retinal ganglion cells. Exosomes were injected weekly into the rats' vitreous, the fluid within the center of the eye. Prior to injection, the exosomes were fluorescently labelled allowing the researchers to track the delivery of the exosome cargo into the retinal ganglion cells. Exosome-treated rats lost about a third of their retinal ganglion cells following optic nerve injury, compared with a 90-percent loss among untreated rats. Stem cell exosome-treated retinal ganglion cells also maintained function, according to electroretinography, which measures electrical activity of retinal cells. The researchers determined that the protective effects of exosomes are mediated by microRNA, molecules that interfere with or silence gene expression. Further research is needed to understand more about the specific contents of the exosomes.